Process for preparing 5-amino-2,4,6-triiodoisophthalic acid dichloride by chlorination of the corresponding acid in the presence of a tertiary amine salt or quaternary ammonium salt

ABSTRACT

A process for the preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride by chlorinating 5-amino-2,4,6-triiodoisophthalic acid with thionyl chloride in the presence of a suitable solvent and of a tertiary amine salt or quaternary ammonium salt in a molar ratio from 1;1 to 1;2 with respect to 5-amino-2,4,6-triiodoisophathalic acid is described. 5-amino-2,4,6-triiodoisophthalic acid dichloride is an intermediate useful for the preparation of iodinated contrast agents.

This application is a 371 of PCT/EP95/04635 filed 24 Nov. 1995.

The present invention relates to a process for the preparation of anintermediate useful in the synthesis of organic compounds and, moreparticularly, it relates to a process for the preparation of5-amino-2,4,6-triiodoisophthalic acid dichloride.

5-Amino-2,4,6-triiodoisophthalic acid dichloride is a known compounduseful for the preparation of iodinated contrast agents among whichIopamidol (British patent No. 1,472,050--Savac AG) and Ioversol(European patent application No. 0083964 Mallinckrodt Inc.) can becited.

Several examples of synthesis of 5-amino-2,4,6-triiodoisophthalic aciddichloride are reported in the literature and all of them foresee thechlorination of 5-amino-2,4,6-triiodoisophthalic acid with thionylchloride.

In particular, we can cite the syntheses described in the alreadymentioned British patent No. 15 1,472,050, in the Belgian patent No.852,418 (Mallinckrodt Inc.) and in the U.S. Pat. No. 3,655,752 (SterlingDrug Inc.) which use a strong excess of thionyl chloride and whichrequire a long and cumbersome work up, hardly suitable under anindustrial viewpoint, even if in some cases they allow to afford thedesired dichloride with high yields.

The synthesis described in the European patent application No. 0118347(Guerbet S.A.) foresees the use of excess thionyl chloride too, but inthe presence of catalytic amounts of N,N-dimethylformamide. The yieldsare high but the work up requires the removal of excess thionyl chlorideby evaporation also in this case.

The use of solvents such as ethyl acetate, as described in theInternational patent applications No. WO 91/09007 (Mallinckrodt Inc.)and No. WO 93/10825 (Mallinckrodt Inc.) or in the already mentionedEuropean patent application No. 0083964, does not allow to obtain thedesired dichloride with satisfactory yields.

We have now found that, by carrying out the chlorination reaction of5-amino-2,4,6-triiodoisophthalic acid with thionyl chloride in asuitable solvent in the presence of a tertiary amine salt or quaternaryammonium salt, the corresponding dichloride is obtained not only in highyields but also substantially free from impurities and in crystallineform by simple dilution of the reaction mixture with water.

Therefore, object of the present invention is a process for thepreparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride bychlorination of 5-amino-2,4,6-triiodoisophthalic acid with thionylchloride in the presence of a solvent characterized in that the reactionis carried out in the presence of a tertiary amine salt or quatemaryammonium salt in a molar ratio from 1:1 to 1:2 with respect to5-amino-2,4,6-triiodoisophthalic acid.

The 5-amino-2,4,6-triiodoisophthalic acid dichloride obtained accordingto the process of the present invention is useful as intermediate in thesynthesis of Iodinated contrast agents.

The amount of thionyl chloride used in the process object of the presentinvention is generally from 2 to 8 moles with respect to5-amino-2,4,6-triiodoisophthalic acid.

Preferably, from 4 to 6 moles of thionyl chloride by mole of5-amino-2,4,6-triiodoisophthalic acid are used.

Tertiary amine salts which can be used in the process object of thepresent invention are generally hydrohalides, preferably hydrochloridesor hydrobromides.

Quaternary ammonium salts which can be used in the process object of thepresent invention are generally halides, preferably chlorides orbromides.

The tertiary amines are generally trialkylamines, preferablytrethylamine.

Quatemary ammonium salts are generally tetraalkvlammonium salts,preferably tetraethylammonium or tetrabutylammoniuum salts.

Examples of tertiary amine salts and of quatemary ammonium salts used inthe process object of the present invention are triethylaminehydrochloride, triethylamine hydrobromide, tetrabutylammonium chloride,tetrabutylammonium bromide, tetraethylammonium bromide andtetraethylammonium chloride.

Preferably triethylamine hydrochloride, which can be optionally preparedin situ, is used. The amount of tertiary amine salt or quatemaryammonium salt is preferably equimolar (molar ratio 1:1) with respect to5-amino-2,4,6-triiodoisophthalic acid. Suitable solvents are ethylacetate, methylene chloride, chloroform and 1,2-dichloroethane.Preferably methylene chloride is used.

A preferred practical embodiment of the present invention is thefollowing. Thionyl chloride is added to a suspension of5-amino-2,4,6-triiodoisophthalic acid, triethylamine and methylenechloride and the reaction mixture is heated under reflux for some hours.

At the end of the addition, water is added and the precipitation of acrystalline product is observed.

By simple filtration and washing, 5-amino-2,4,6-triiodoisophthalic aciddichloride is obtained in pure form.

The characterizing feature of the process object of the invention is thepresence of amounts at least equimolar of a tertiary amine salt or of aquatemary amine salt.

The use of said salt in the above indicated amounts allows to obtain thedesired product with extremely high yields and, above all, free fromimpurities which should make difficult its isolation with a puritydegree suitable for its use as intermediate in the synthesis ofiodinated contrast agents.

It is worth underlining that the substantial absence of by-products inthe reaction of preparation of 5-amino-2,4,6-triiodoisophthalic aciddichloride according to the process object of the present invention doesnot result exclusively in an improvement of the overall yield of theprocess with respect to the known methods, but allows also the isolationof the desired product with simple operations of dilution in water ofthe reaction mixture.

It is evident to the man skilled in the art the advantage deriving fromthe possibility of carrying out a process for the synthesis of anintermediate with high yields, high purity, through extremely simpleoperations, without requiring either the removal of thionyl chloride byevaporation or repeated purification operations for isolating thedesired product in pure form.

As already underlined, contrary to what described in the known processesfor the preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride,the isolation of the pure product is carried out by simple dilution withwater of the reaction mixture.

As far as we know, a mechanism able to explain the unexpected advantagesderiving from the use of a tertiary amine salt or of a quaternaryammonium salt according to the process object of the present inventioncannot be assumed.

Probably, the salt forms an adduct with thionyl chloride.

In this connection, it is worth noting that the literature (Europeanpatent application No. 0026281--Bracco Industria Chimica S.p.A.)describes the preparation of 5-methylamino2,4,6-triiodoisophthalic aciddichloride by reaction with thionyl chloride in the presence of smallamounts of quinoline, without reporting the yields yet.

However, the use of quinoline or of a tertiary amine salt or quatemaryammoniun salt in molar amounts significantly lower than 1:1 with respectto 5-amino-2,4,6-triiodoisophthalic acid does not allow to obtain thedesired product with high yields and, above all, with a suitable puritydegree. In particular, by using quinoline in catalytic amounts asdescribed in the European patent application No. 0026281, the desireddichloride is obtained in admixture with not negligible amounts ofby-products and then with a purity degree not suitable for the use asintermediate in the subsequent steps of the process for the preparationof iodinated contrast agents.

In order to illustrate the present invention the following examples arenow given.

EXAMPLE 1

Methylene chloride (280 g), triethylamine (25.5 g; 0.25 moles) and water(2.25 g; 0.125 moles) were charged in this order into a reactor.

After addition of thionyl chloride (14.9 g; 0.125 moles) dropwise whilekeeping the temperature below 30° C., 5-amino-2,4,6-triiodoisophthalicacid (140 g; 0.25 moles) and, in about 1.5 hours, thionyl chloride (143g; 1.2 moles) were added while keeping the internal temperature below36° C. and adjusting the addition rate with the gas emission.

At the end of the addition, the reaction mixture was kept under reflux(43° C.) for 28 hours. After cooling to about 30° C., methylene chloride(65 g) and, in small portions, water (100 g) were added.

At about half of the addition, the formation of a crystallineprecipitate was observed.

After filtration, the resultant product was reduced to pulp with water(200 g) and then dried in oven under vacuum at 60° C. for about 21 hoursobtaining 5-amino-2,4,6-triiodoisophthalic acid dichloride (139 g; 93.3%yield) practically pure by HPLC analysis and by thin layerchromatography.

EXAMPLE 2

Methylene chloride (280 g), triethylamine (51 g; 0.5 moles) and water(4.5 g; 0.25 moles) were charged in this order into a reactor.

After addition of thionyl chloride (30 g; 0.25 moles) dropwise whilekeeping the temperature below 30° C., 5-amino-2,4,6-triiodoisophthalicacid (140 g; 0.25 moles) and, in about 2 hours, thionyl chloride (143 g;1.2 moles) were added while keeping the internal temperature below 36°C. and adjusting the addition rate with the gas emission.

At the end of the addition, the reaction mixture was kept under reflux(about 43° C.) for 22 hours.

After cooling to about 30° C., water (100 g) was added in smallportions.

At about half of the addition, the formation of a crystallineprecipitate was observed.

Subsequently, the addition of water (250 g total) was completed and theprecipitate was filtered.

The resultant product was reduced to pulp twice with water (2×300 g) andthen dried in oven under vacuum at 60° C. for about 21 hours obtaining5-amino-2,4,6-triiodoisophthalic acid dichloride (140.7 g; 94.4% yield)practically pure by HPLC analysis and by thin layer chromatography.

EXAMPLE 3

Methylene chloride (112 g) and tetrabutylammonium bromide (3.23 g; 0.1moles) were charged in this order into a reactor.

5-Amino-2,4,6-triiodoisophthalic acid (55.9 g; 0.1 moles) and, in about2 hours, thionyl chloride (57.1 g; 0.479 moles) were added to themixture while keeping the internal temperature below 36° C. andadjusting the addition rate with the gas emission.

At the end of the addition. the reaction mixture was kept under reflux(43° C.) for 27 hours.

After cooling to about 20° C., water (60 g) was added in small portions.

At about half of the addition, the formation of a crystallineprecipitate was observed.

After filtration, the resultant product was washed with water (5×50 g)and then dried in oven under vacuum at 50° C. for about 21 hoursobtaining 5-amino-2,4,6-triiodoisophthalic acid dichloride (49.99 g;83.8% yield) practically pure by HPLC analysis and by thin layerchromatography.

We claim:
 1. A process for the preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride by chlorination of 5-amino-2,4,6-triiodoisophthalic acid with thionyl chloride in the presence of a solvent characterized in that the reaction is carried out in the presence of a tertiary amine salt or quaternary ammonium salt in a molar ratio from 1:1 to 1:2 with respect to 5-amino-2,4,6-triiodoisophthalic acid.
 2. A process according to claim 1 wherein the amount of thionyl chloride is from 2 to 8 moles by mole of 5-amino-2,4,6-triiodoisophthalic acid.
 3. A process according to claim 2 wherein the amount of thionyl chloride is from 4 to 6 moles by mole of 5-amino-2,4,6-triiodoisophthalic acid.
 4. A process according to claim 1 wherein the tertiary amine salts or quaternary amine salts are tertiary amine hydrohalides or quaternary ammonium halides.
 5. A process according to claim 4 wherein the salts are tertiary amine hydrochlorides or hydrobromides or quaternary ammonium chlorides or bromides.
 6. A process according to claim 1 wherein the tertiary amines are trialkylamines.
 7. A process according to claim 6 wherein the tertiary amine is triethylamine.
 8. A process according to claim 1 wherein the quaternary ammonium salts are tetraalkylammonium salts.
 9. A process according to claim 8 wherein the quaternary ammonium salt is selected among tetraethylammonium and tetrabutylammonium salts.
 10. A process according to claim 1 wherein the tertiary amine salts or quaternary ammonium salts are selected among triethylamine hydrochloride, triethylamine hydrobromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylammonium bromide and tetraethylammonium chloride.
 11. A process according to claim 10 wherein triethylamine hydrochloride is used.
 12. A process according to claim 1 wherein the amount of tertiary amine salt or quaternary ammonium salt is equimolar with respect to 5-amino-2,4,6-triiodoisophthalic acid.
 13. A process according to claim 1 wherein the solvent is selected among ethyl acetate, methylene chloride, chloroform and 1,2-dichloroethane.
 14. A process according to claim 13 wherein the solvent is methylene chloride. 